2. Academic Validation
  3. Astragali radix - Curcumae rhizoma herb pair suppresses hepatocellular carcinoma through EGFR/AKT/mTOR pathway and induces lipid peroxidation-related ferroptosis via HIF-1α/HO-1/GPX4 axis

Astragali radix - Curcumae rhizoma herb pair suppresses hepatocellular carcinoma through EGFR/AKT/mTOR pathway and induces lipid peroxidation-related ferroptosis via HIF-1α/HO-1/GPX4 axis

  • J Ethnopharmacol. 2025 May 28:348:119912. doi: 10.1016/j.jep.2025.119912.
Chen Wang 1,  Chen-Hao Shi 1,  Hao-Yang Bai 1,  Jun Lu 1,  Hong-Tao Hu 1,  Yu-Mei Sun 1,  Hang Gao 2,  Hai An 2,  Jia-Hui Lu 1,  Hua-Jun Zhao 3,  Zhi-Hui Zhu 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
  • 2 Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
  • 3 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. Electronic address: zhj@zcmu.edu.cn.
  • 4 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China. Electronic address: zhuzhihui@zcmu.edu.cn.
PMID: 40316156 DOI: 10.1016/j.jep.2025.119912
Abstract

Ethnopharmacological relevance: The Astragali Radix - Curcumae Rhizoma herb pair (ACHP) originated from the famous traditional Chinese medicine text "YiXueZhongZhongCanXiLu", in which the two herbs were paired to form Chinese herbal compounds commonly used clinically for digestive system tumors, such as hepatocellular carcinoma (HCC). Although ACHP has been inherited for thousands of years in China, its mechanism against HCC remains unclear.

Aim of the study: The study aims to evaluate the effect and explore the mechanism of ACHP against HCC.

Methods: The efficacy and safety of ACHP against HCC in vivo were evaluated by tumor volume, organ index, H&E staining, hepatic and renal factors. The serum metabolites of ACHP were identified by UPLC-Q-TOF-MS/MS. The key targets and potential mechanisms of ACHP against HCC were screened by transcriptomics, network pharmacology and molecular docking. The effect and induction of Ferroptosis of ACHP-containing serum on HCC in vitro was evaluated by MTT, colony formation assay and specific detection kits. The expression of ferroptosis-related proteins and pathways in vivo was detected by immunohistochemistry.

Results: ACHP significantly inhibited tumor proliferation compared to the two herbs used separately, and showed a favorable safety profile. A total of 75 serum metabolites were identified in both positive and negative ion modes. Transcriptomics results revealed that Ferroptosis played a key role in the anti-HCC process of ACHP. Network pharmacology and molecular docking results suggested that the anti-HCC effect of ACHP may be related to EGFR/Akt/mTOR pathway and HIF-1α/HO-1/GPX4 axis. In vitro and in vivo experiments further demonstrated that ACHP suppressed oncogenic signaling via the EGFR/Akt/mTOR pathway while inducing lipid peroxidation-related Ferroptosis through HIF-1α/HO-1/GPX4 axis, thereby inhibiting HepG2 cells proliferation and HCC mice tumor growth.

Conclusion: ACHP exerts its effects by suppressing oncogenic signaling through the EGFR/Akt/mTOR pathway and inducing lipid peroxidation-related Ferroptosis in HCC via the HIF-1α/HO-1/GPX4 axis. This systematic investigation establishes a coherent pharmacological chain from compound identification to mechanism verification, highlighting ACHP's therapeutic potential as a Ferroptosis inducer targeting oncogenic signaling networks in HCC.

Keywords

Astragali Radix; Curcumae Rhizoma herb pair; EGFR/AKT/mTOR pathway; Ferroptosis; HIF-1α/HO-1/GPX4 axis; Hepatocellular carcinoma.

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